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Abstract Objective The resting‐state functional connectome has not been extensively investigated in amyotrophic lateral sclerosis (ALS) spectrum disease, in particular in relationship with patients' genetic status. Methods Here we studied the network‐to‐network connectivity of 19 ALS patients carrying the C9orf72 hexanucleotide repeat expansion (C9orf72+), 19 ALS patients not affected by C9orf72 mutation (C9orf72−), and 19 ALS‐mimic patients (ALSm) well‐matched for demographic and clinical variables. Results When compared with ALSm, we observed greater connectivity of the default mode and frontoparietal networks with the visual network for C9orf72+ patients (P = 0.001). Moreover, the whole‐connectome showed greater node degree (P

Abstract Background Systemic inflammation has been proposed as a relevant mechanism in amyotrophic lateral sclerosis (ALS). Still, comprehensive data on ALS patients' innate and adaptive immune responses and their effect on the clinical phenotype are lacking. Here, we investigate systemic immunity in a population‐based ALS cohort using readily available hematological indexes. Methods We collected clinical data and the complete blood count (CBC) at diagnosis in ALS patients from the Piemonte and Valle d'Aosta Register for ALS (PARALS) from 2007 to 2019. Leukocytes populations, neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), systemic‐immune‐inflammation index (SII), and lymphocyte‐to‐monocyte ratio (LMR) were derived from CBC. All variables were analyzed for association with clinical features in the entire cohort and then in sex‐ and age‐based subgroups. Results Neutrophils (P = 0.001) and markers of increased innate immunity (NLR, P = 0.008 and SII, P = 0.006) were associated with a faster disease progression. Similarly, elevated innate immunity correlated with worse pulmonary function and shorter survival. The prognosis in women also correlated with low lymphocytes (P = 0.045) and a decreased LMR (P = 0.013). ALS patients with cognitive impairment exhibited lower monocytes (P = 0.0415). Conclusions and Relevance The dysregulation of the systemic immune system plays a multifaceted role in ALS. More specifically, an elevated innate immune response is associated with faster progression and reduced survival. Conversely, ALS patients with cognitive impairment showed a reduction in monocyte count. Additionally, immune response varied according to sex and age, thus suggesting that involved immune pathways are patient specific. Further studies will help translate those findings into clinical practice or targeted treatments.

Consumer knowledge of mental health conditions, awareness of mental health support services, and perception of community pharmacists’ role in mental health promotion. Conocimiento del consumidor sobre las condiciones de salud mental, conocimiento de los servicios de apoyo a la salud mental y percepción del papel de los farmacéuticos comunitarios en la promoción de la salud mental. Singleton J, Stevens J, Truong R, McCulloch A, Ara E, Cooper M, Hobbs B, Hotham E, Suppiah V. https://doi.org/10.1093/ijpp/riad091 Community pharmacy and primary health care - Types of integration and their applicability: A narrative review. Farmacia comunitaria y atención primaria de salud - Tipos de integración y su aplicabilidad: una revisión narrativa Urionagüena A, Piquer-Martínez C, Gastelurrutia MA, Benrimoj SI, García-Cárdenas V, Fernández-Llimos F, Martínez-Martínez F, Calvo B. https://doi.org/10.1016/j.sapharm.2022.10.007 What helps, what hinders antidepressant discontinuation? Qualitative analysis of patients’ experiences and expectations. ¿Qué ayuda y qué dificulta la interrupción de los antidepresivos? Análisis cualitativo de las experiencias y expectativas de los pacientes. Meißner C, Meyrose AK, Nestoriuc Y. https://doi.org/10.3399/BJGP.2023.0020

Abstract In preclinical studies rapamycin was found to target neuroinflammation, by expanding regulatory T cells, and affecting autophagy, two pillars of amyotrophic lateral sclerosis (ALS) pathogenesis. Herein we report a multicenter, randomized, double-blind trial, in 63 ALS patients who were randomly assigned in a 1:1:1 ratio to receive rapamycin 2 mg/m2/day,1 mg/m2/day or placebo (EUDRACT 2016-002399-28; NCT03359538). The primary outcome, the number of patients exhibiting an increase >30% in regulatory T cells from baseline to treatment end, was not attained. Secondary outcomes were changes from baseline of T, B, NK cell subpopulations, inflammasome mRNA expression and activation status, S6-ribosomal protein phosphorylation, neurofilaments; clinical outcome measures of disease progression; survival; safety and quality of life. Of the secondary outcomes, rapamycin decreased mRNA relative expression of the pro-inflammatory cytokine IL-18, reduced plasmatic IL-18 protein, and increased the percentage of classical monocytes and memory switched B cells, although no corrections were applied for multiple tests. In conclusion, we show that rapamycin treatment is well tolerated and provides reassuring safety findings in ALS patients, but further trials are necessary to understand the biological and clinical effects of this drug in ALS.

Experiencia con la medicación e intervenciones clínicas en pacientes valorados por farmacéuticos: revisión de alcance Orozco-Solano S, Silva-Castro MM, Machuca M. DOI: https://doi.org/10.1016/j.farma.2023.04.009 Artificial Intelligence (AI) in Pharmacy: An Overview of Innovations Raza MA, Aziz S, Noreen M, Saeed A, Anjum I, Ahmed M, Raza SM. DOI: 10.24926/iip.v13i2.4839 Pharmacist-Physician Interprofessional Collaboration to Promote Early Detection of Cognitive Impairment: Increasing Diagnosis Rate Ramos H, Pardo J, Sánchez R, Puchades E, Pérez-Tur J, Navarro A, Moreno L. https://doi.org/10.3389/fphar.2021.579489

Abstract Background Thromboelastometry is considered the best method to assesses hemostasis in liver disease. Diagnostic performance could be improved by adding protein C activators such as thrombomodulin or Protac®. We assessed changes in ROTEM parameters after the addition of Protac® in patients with acute-on-chronic liver failure (ACLF), acute decompensation (AD), and healthy individuals (HI) to define different hemostasis patterns, considering standard and velocity ROTEM parameters, and assess whether Protac® can improve the definition of the pattern. Methods Pre-test, we investigated whether diluted EXTEM reagent improved the effect of Protac® on the clotting time (CT)-ratio with and without Protac®. Ten ACLF and 20 AD patients and 21 HI were included in the main study. Results Standard EXTEM was used in the main study. INTEM CFT, INTEM A5 (inverse), and INTEM TPI (inverse) were the parameters that best differentiated liver disease from HI (ROC AUC, 0.921, 0.906, and 0.928, respectively; all P-values

Background: In clinical practice, the implementation of tailored treatment is crucial for assessing the patient’s emotional processing profile. Here, we investigate all three levels of analysis characterizing emotion processing, i.e., recognition, representation, and regulation, in patients with peripheral neuropathic pain (PNP). Methods: Sixty-two patients and forty-eight healthy controls underwent quantitative sensory testing, i.e., psychophysical tests to assess somatosensory functions such as perception of cold (CDT), heat-induced pain (HPT), and vibration (VDT), as well as three standardized tasks to assess emotional processing: (1) the Ekman 60-Faces Test (EK-60F) to assess recognition of basic facial emotions, (2) the Reading the Mind in the Eyes Test (RME) to assess the ability to represent the feelings of another person by observing their eyes, and (3) the 20-item Toronto Alexithymia Scale (TAS-20) to assess emotional dysregulation, i.e., alexithymia. Results: General Linear Model analysis revealed a significant relationship between left index finger VDT z-scores in PNP patients with alexithymia. The RME correlated with VDT z-scores of the left little finger and overall score for the EK-60F. Conclusions: In patients with PNP, emotion processing is impaired, which emphasizes the importance of assessing these abilities appropriately in these patients. In this way, clinicians can tailor treatment to the needs of individual patients.

Respiratory failure assessment is among the most debatable research topics in amyotrophic lateral sclerosis (ALS) clinical research due to the wide heterogeneity of its presentation. Among the different pulmonary function tests (PFTs), maximal voluntary ventilation (MVV) has shown potential utility as a diagnostic and monitoring marker, able to capture early respiratory modification in neuromuscular disorders. In the present study, we explored calculated MVV (cMVV) as a prognostic biomarker in a center-based, retrospective ALS population belonging to the Piemonte and Valle d’Aosta registry for ALS (PARALS). A Spearman’s correlation analysis with clinical data and PFTs showed a good correlation of cMVV with forced vital capacity (FVC) and a moderate correlation with some other features such as bulbar involvement, ALSFRS-R total score, blood oxygen (pO2), carbonate (HCO3−), and base excess (BE), measured with arterial blood gas analysis. Both the Cox proportional hazard models for survival and the time to non-invasive ventilation (NIV) measurement highlighted that cMVV at diagnosis (considering cMVV(40) ≥ 80) is able to stratify patients across different risk levels for death/tracheostomy and NIV indication, especially considering patients with FVC% ≥ 80. In conclusion, cMVV is a useful marker of early respiratory failure in ALS, and is easily derivable from standard PFTs, especially in asymptomatic ALS patients with normal FVC measures.

Respiratory failure is the most common cause of death in patients with amyotrophic lateral sclerosis (ALS) and occurs with great variability among patients according to different phenotypic features. Early predictors of respiratory failure in ALS are important to start non-invasive ventilation (NIV). Venous serum chloride values correlate with carbonate (HCO3-) blood levels and reflect metabolic compensation of respiratory acidosis. Despite its wide availability and low cost, few data on serum chloride as a prognostic marker exist in ALS literature. In the present study, we evaluated serum chloride values at diagnosis as prognostic biomarkers for overall survival and NIV adaptation in a retrospective center-based cohort of ALS patients. We collected all ALS patients with serum chloride assessment at diagnosis, identified through the Piemonte and Valle d’Aosta Register for ALS, evaluating the correlations among serum chloride, clinical features, and other serum biomarkers. Thereafter, time-to-event analysis was modeled to predict overall survival and NIV start. We found a significant correlation between serum chloride and inflammatory status markers, serum sodium, forced vital capacity (FVC), ALS functional rating scale-revised (ALSFRS-R) item 10 and 11, age at diagnosis, and weight loss. Time-to-event analysis confirmed both in univariate analysis and after multiple confounders’ adjustment that serum chloride value at diagnosis significantly influenced survival and time to NIV start. According to our analysis, based on a large ALS cohort, we found that serum chloride analyzed at diagnosis is a low-cost marker of impending respiratory decompensation. In our opinion, it should be added among the serum prognostic biomarkers that are able to stratify patients into different prognostic categories even when performed in the early phases of the disease.

Abstract The aetiology of Amyotrophic Lateral Sclerosis (ALS) is still poorly understood. The discovery of genetic forms of ALS pointed out the mechanisms underlying this pathology, but also showed how complex these mechanisms are. Excitotoxicity is strongly suspected to play a role in ALS pathogenesis. Excitotoxicity is defined as neuron damage due to excessive intake of calcium ions (Ca2+) by the cell. This study aims to find a relationship between the proteins coded by the most relevant genes associated with ALS and intracellular Ca2+ accumulation. In detail, the profile of eight proteins (TDP-43, C9orf72, p62/sequestosome-1, matrin-3, VCP, FUS, SOD1 and profilin-1), was analysed in three different cell types induced to raise their cytoplasmic amount of Ca2+. Intracellular Ca2+ accumulation causes a decrease in the levels of TDP-43, C9orf72, matrin3, VCP, FUS, SOD1 and profilin-1 and an increase in those of p62/sequestosome-1. These events are associated with the proteolytic action of two proteases, calpains and caspases, as well as with the activation of autophagy. Interestingly, Ca2+ appears to both favour and hinder autophagy. Understanding how and why calpain-mediated proteolysis and autophagy, which are physiological processes, become pathological may elucidate the mechanisms responsible for ALS and help discover new therapeutic targets.

Objective: C9orf72 mutation carriers with different neurological phenotypes show cortical and subcortical atrophy in multiple different brain regions, even in pre-symptomatic phases. Despite there is a substantial amount of knowledge, small sample sizes, clinical heterogeneity, as well as different choices of image analysis may hide anatomical abnormalities that are unique to amyotrophic lateral sclerosis (ALS) patients with this genotype or that are indicative of the C9orf72-specific trait overlain in fronto-temporal dementia patients. Methods: Brain structural and resting state functional magnetic imaging was obtained in 24 C9orf72 positive (ALSC9+) ALS patients paired for burden disease with 24 C9orf72 negative (ALSC9-) ALS patients. A comprehensive structural evaluation of cortical thickness and subcortical volumes between ALSC9+ and ALSC9- patients was performed while a region of interest (ROI)-ROI analysis of functional connectivity was implemented to assess functional alterations among abnormal cortical and subcortical regions. Results were corrected for multiple comparisons. Results: Compared to ALSC9- patients, ALSC9+ patients exhibited extensive disease-specific patterns of thalamo-cortico-striatal atrophy, supported by functional alterations of the identified abnormal regions. Cortical thinning was most pronounced in posterior areas and extended to frontal regions. Bilateral atrophy of the mediodorsal and pulvinar nuclei was observed, emphasizing a focal rather than global thalamus atrophy. Volume loss in a large portion of bilateral caudate and left putamen was reported. The marked reduction of functional connectivity observed between the left posterior thalamus and almost all the atrophic cortical regions support the central role of the thalamus in the pathogenic mechanism of C9orf72-mediated disease. Conclusions: These findings constitute a coherent and robust picture of ALS patients with C9orf72-mediated disease, unveiling a specific structural and functional characterization of thalamo-cortico-striatal circuit alteration. Our study introduces new evidence in the characterization of the pathogenic mechanisms of C9orf72 mutation.

BackgroundCoronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with disorders affecting the peripheral and the central nervous system. A high number of patients develop post-COVID-19 syndrome with the persistence of a large spectrum of symptoms, including neurological, beyond 4 weeks after infection. Several potential mechanisms in the acute phase have been hypothesized, including damage of the blood-brain-barrier (BBB). We tested weather markers of BBB damage in association with markers of brain injury and systemic inflammation may help in identifying a blood signature for disease severity and neurological complications.MethodsBlood biomarkers of BBB disruption (MMP-9, GFAP), neuronal damage (NFL) and systemic inflammation (PPIA, IL-10, TNFα) were measured in two COVID-19 patient cohorts with high disease severity (ICUCovid; n=79) and with neurological complications (NeuroCovid; n=78), and in two control groups free from COVID-19 history, healthy subjects (n=20) and patients with amyotrophic lateral sclerosis (ALS; n=51). Samples from COVID-19 patients were collected during the first and the second wave of COVID-19 pandemic in Lombardy, Italy. Evaluations were done at acute and chronic phases of the COVID-19 infection.ResultsBlood biomarkers of BBB disruption and neuronal damage are high in COVID-19 patients with levels similar to or higher than ALS. NeuroCovid patients display lower levels of the cytokine storm inducer PPIA but higher levels of MMP-9 than ICUCovid patients. There was evidence of different temporal dynamics in ICUCovid compared to NeuroCovid patients with PPIA and IL-10 showing the highest levels in ICUCovid patients at acute phase. On the contrary, MMP-9 was higher at acute phase in NeuroCovid patients, with a severity dependency in the long-term. We also found a clear severity dependency of NFL and GFAP levels, with deceased patients showing the highest levels.DiscussionThe overall picture points to an increased risk for neurological complications in association with high levels of biomarkers of BBB disruption. Our observations may provide hints for therapeutic approaches mitigating BBB disruption to reduce the neurological damage in the acute phase and potential dysfunction in the long-term.

Background: Dropping objects from hands (DOH) is a common symptom of carpal tunnel syndrome (CTS). We evaluated the clinical, neurophysiological, and psychophysiological features of 120 CTS patients to elucidate the DOH pathophysiology. Forty-nine healthy controls were included. Methods: In the patients, the Boston Carpal Tunnel Questionnaire (BCTQ), the Douleur Neuropathique 4 questions (DN4), and a numeric rating scale for pain (NRS) were evaluated. In patients and controls, we evaluated bilateral median and ulnar motor and sensory nerve conduction studies, cutaneous silent period and cutaneomuscular reflexes (CMR) of the abductor pollicis brevis, cold-detection threshold (CDT) and heat-pain detection threshold (HPT) at the index, little finger, and dorsum of the hand, and vibratory detection threshold at the index and little finger by quantitative sensory testing. Results: CTS with DOH had higher BCTQ, DN4 and NRS, lower median sensory action potential, longer CMR duration, lower CDT and higher HPT at all tested sites than controls and CTS without DOH. Predictive features for DOH were abnormal CDT and HPT at the right index and dorsum (OR: 3.88, p: 0.03) or at the little finger (OR: 3.27, p: 0.04) and a DN4 higher than 4 (OR: 2.16, p < 0.0001). Conclusions: Thermal hypoesthesia in median and extra-median innervated territories and neuropathic pain are predictive of DOH in CTS.

BackgroundAmyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative rare disease that affects motor neurons in the brain, brainstem, and spinal cord, resulting in progressive weakness and atrophy of voluntary skeletal muscles. Although much has been achieved in understanding the disease pathogenesis, treatment options are limited, and in Europe, riluzole is the only approved drug. Recently, some other drugs showed minor effects.MethodsThe TUDCA-ALS trial is a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The study aims to enroll 320 patients in 25 centers across seven countries in Europe. Enrolled patients are randomized to one of two treatment arms: TUDCA or identical placebo by oral route. The study measures disease progression during the treatment period and compares it to natural progression during a no-treatment run-in phase. Clinical data and specific biomarkers are measured during the trial. The study is coordinated by a consortium composed of leading European ALS centers.ConclusionThis trial is aimed to determine whether TUDCA has a disease-modifying activity in ALS. Demonstration of TUDCA efficacy, combined with the validation of new biomarkers, could advance ALS patient care.Clinical trial registrationClinicalTrials.gov, identifier: NCT03800524.

Abstract Background Amyotrophic lateral sclerosis (ALS) is a multifactorial, multisystem motor neuron disease for which currently there is no effective treatment. There is an urgent need to identify biomarkers to tackle the disease’s complexity and help in early diagnosis, prognosis, and therapy. Extracellular vesicles (EVs) are nanostructures released by any cell type into body fluids. Their biophysical and biochemical characteristics vary with the parent cell’s physiological and pathological state and make them an attractive source of multidimensional data for patient classification and stratification. Methods We analyzed plasma-derived EVs of ALS patients (n = 106) and controls (n = 96), and SOD1G93A and TDP-43Q331K mouse models of ALS. We purified plasma EVs by nickel-based isolation, characterized their EV size distribution and morphology respectively by nanotracking analysis and transmission electron microscopy, and analyzed EV markers and protein cargos by Western blot and proteomics. We used machine learning techniques to predict diagnosis and prognosis. Results Our procedure resulted in high-yield isolation of intact and polydisperse plasma EVs, with minimal lipoprotein contamination. EVs in the plasma of ALS patients and the two mouse models of ALS had a distinctive size distribution and lower HSP90 levels compared to the controls. In terms of disease progression, the levels of cyclophilin A with the EV size distribution distinguished fast and slow disease progressors, a possibly new means for patient stratification. Immuno-electron microscopy also suggested that phosphorylated TDP-43 is not an intravesicular cargo of plasma-derived EVs. Conclusions Our analysis unmasked features in plasma EVs of ALS patients with potential straightforward clinical application. We conceived an innovative mathematical model based on machine learning which, by integrating EV size distribution data with protein cargoes, gave very high prediction rates for disease diagnosis and prognosis.

Background: The management of a difficult airway requires training in cricothyroidotomy (CT). The objectives of this study were: (i) to describe technical changes made to The REAL CRIC Trainer model in order to increase its realism, (ii) to assess the model by experts in comparison to a commercial dry model, (iii) to evaluate its performance in a realistic simulation scenario for training technical and behavioural skills, and (iv) to assess whether the model can help to identify anatomic structures by ultrasound (US). Methods: An observational prospective study was conducted in which an assembled modified model was assessed by five experts in CT and comparing it with a commercial dry model. The fidelity of US images obtained in the model was compared to those obtained from volunteers. The usefulness and realism of the model, attached to a high-fidelity simulator's neck in emergent CT clinical scenario, was assessed by the 11 ICU staff taking part. Results: Using a score out of 10, CT performance in our model and in a dry model was rated by the experts as 9 vs. 6, respectively in external appearance, 8.4 vs. 5.8 in tactile fidelity, and 8.6 vs. 4.1 in technical realism. Participants in the simulation gave a mean score of 7.7/10 to the fidelity parameters. Usefulness for training of the model integration into a simulation scenario was rated as 9.6. Ultrasound images were evaluated as high fidelity. Conclusions: Our modified REAL CRIC Trainer model was rated high by experts in CT and participants in a simulated clinical scenario, and may be useful for a complete emergent CT training closer to the clinical reality than the models currently available. Resumen: Introducción: El manejo de la vía aérea difícil comprende el entrenamiento en la cricotiroidotomía (CT). Los objetivos de este estudio fueron: describir los cambios técnicos realizados en el modelo REAL CRIC Trainer para aumentar el realismo, obtener su valoración por expertos respecto a un modelo seco comercializado, evaluar su rendimiento en un escenario de simulación para el entrenamiento de habilidades técnicas y conductuales de la CT emergente y determinar si el modelo permite identificar estructuras anatómicas mediante ecografía. Métodos: Estudio prospectivo y observacional, el modelo ensamblado fue evaluado por 5 expertos en CT que lo compararon con un modelo seco comercial. Se comparó también su fidelidad ecográfica con la de las imágenes obtenidas en voluntario. La utilidad y el realismo del modelo utilizado en un escenario de simulación clínica para CT emergente fue valorada por 11 participantes, personal de la UCI. Resultados: La evaluación por expertos de la CT en el modelo diseñado y en modelo seco comercial, obtuvo puntuaciones de 9 vs. 6 sobre 10, respectivamente en apariencia externa, 8,4 vs. 5,8 en fidelidad táctil y 8,6 vs. 4,1 en realismo de la técnica. Los participantes en la simulación otorgaron una puntuación media de 7,7/10 a los parámetros de fidelidad. La utilidad de integrar el modelo en un escenario de simulación de alta fidelidad fue evaluada en 9,6/10 y las imágenes de ultrasonido fueron consideradas como de alta fidelidad. Conclusiones: El modelo REAL CRIC Trainer modificado fue muy bien valorado tanto por los expertos como por los participantes en un escenario clínico de simulación, y puede ser útil para un entrenamiento completo en CT emergente más próximo a la realidad clínica que los modelos disponibles.

Abstract Background Critically ill patients with COVID-19 are an especially susceptible population to develop post-intensive care syndrome (PICS) due to acute respiratory distress syndrome (ARDS). Patients can suffer acute severe pain and may have long-term mental, cognitive, and functional health deterioration after discharge. However, few controlled trials are evaluating interventions for the prevention and treatment of PICS. The study hypothesis is that a specific care program based on early therapeutic education and psychological intervention improves the quality of life of patients at risk of developing PICS and chronic pain after COVID-19. The primary objective is to determine whether the program is superior to standard-of-care on health-related quality of life at 6 months after hospital discharge. The secondary objectives are to determine whether the intervention is superior to standard-of-care on health-related quality of life, incidence of chronic pain and degree of functional limitation, incidence of anxiety, depression, and post-traumatic stress syndrome at 3 and 6 months after hospital discharge. Methods The PAINCOVID trial is a unicentric randomized, controlled, patient-blinded superiority trial with two parallel groups. The primary endpoint is the health-related quality of life at 6 months after hospital discharge, and randomization will be performed with a 1:1 allocation ratio. This paper details the methodology and statistical analysis plan of the trial and was submitted before outcome data were available. The estimated sample size is 84 patients, 42 for each arm. Assuming a lost to follow-up rate of 20%, a sample size of 102 patients is necessary (51 for each arm). Discussion This is the first randomized clinical trial assessing the effectiveness of an early care therapeutic education, and psychological intervention program for the management of PICS and chronic pain after COVID-19. The intervention will serve as proof of the need to implement early care programs at an early stage, having an incalculable impact given the current scenario of the pandemic. Trial registration This study is being conducted in accordance with the tenets of the Helsinki Declaration and has been approved by the authors’ institutional review board Comité Ético de Investigación Clínica del Hospital Clínic de Barcelona (approval number: HCB/2020/0549) and was registered on May 9, 2020, at clinicaltrials.gov ( NCT04394169 ).

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with motor neuron degeneration, muscle atrophy and paralysis. To date, multiple panels of biomarkers have been described in ALS patients and murine models. Nevertheless, none of them has sufficient specificity and thus the molecular signature for ALS prognosis and progression remains to be elucidated. Here we overcome this limitation through a longitudinal study, analyzing serum levels of circulating miRNAs, stable molecules that are recently used as promising biomarkers for many types of human disorders, in ALS patients during the progression of the pathology. We performed next-generation sequencing (NGS) analysis and absolute RT quantification of serum samples of ALS patients and healthy controls. The expression levels of five selected miRNAs were quantitatively analyzed during disease progression in each patient and we demonstrated that high levels of miR-206, miR-133a and miR-151a-5p can predict a slower clinical decline of patient functionality. In particular, we found that miR-206 and miR-151a-5p serum levels were significantly up-regulated at the mild stage of ALS pathology, to decrease in the following moderate and severe stages, whereas the expression levels of miR-133a and miR-199a-5p remained low throughout the course of the disease, showing a diagnostic significance in moderate and severe stages for miR-133a and in mild and terminal ones for miR-199a-5p. Moreover, we found that miR-423–3p and 151a-5p were significantly downregulated respectively in mild and terminal stages of the disease. These data suggest that these miRNAs represent potential prognostic markers for ALS disease.

Abstract Background Clinical registers constitute an invaluable resource in the medical data-driven decision making context. Accurate machine learning and data mining approaches on these data can lead to faster diagnosis, definition of tailored interventions, and improved outcome prediction. A typical issue when implementing such approaches is the almost unavoidable presence of missing values in the collected data. In this work, we propose an imputation algorithm based on a mutual information-weighted k-nearest neighbours approach, able to handle the simultaneous presence of missing information in different types of variables. We developed and validated the method on a clinical register, constituted by the information collected over subsequent screening visits of a cohort of patients affected by amyotrophic lateral sclerosis. Methods For each subject with missing data to be imputed, we create a feature vector constituted by the information collected over his/her first three months of visits. This vector is used as sample in a k-nearest neighbours procedure, in order to select, among the other patients, the ones with the most similar temporal evolution of the disease over time. An ad hoc similarity metric was implemented for the sample comparison, capable of handling the different nature of the data, the presence of multiple missing values and include the cross-information among features captured by the mutual information statistic. Results We validated the proposed imputation method on an independent test set, comparing its performance with those of three state-of-the-art competitors, resulting in better performance. We further assessed the validity of our algorithm by comparing the performance of a survival classifier built on the data imputed with our method versus the one built on the data imputed with the best-performing competitor. Conclusions Imputation of missing data is a crucial –and often mandatory– step when working with real-world datasets. The algorithm proposed in this work could effectively impute an amyotrophic lateral sclerosis clinical dataset, by handling the temporal and the mixed-type nature of the data and by exploiting the cross-information among features. We also showed how the imputation quality can affect a machine learning task.

The following article analyzes the philosophical conception of Plato and Plotinus about beauty and its correspondence with Greek art. The Platonic position discusses the beautiful according to the guidelines of harmony, order, symmetry and proportion, so that, if it can allude to a preponderance of ethos, it has a sculptural correlation with the classical period. For his part, Plotinus bases the beauty on the basis of a multiple appreciation, that is, he admits pathos, an aspect that is linked to Hellenistic sculpture. According to the previous one, a dialogue will be established between the philosophical discourse and the artistic representation.

Background: Data from published studies about the effect of HFE polymorphisms on ALS risk, phenotype, and survival are still inconclusive. We aimed at evaluating whether the p.H63D polymorphism is a modifier of phenotype and survival in SOD1-mutated patients. Methods: We included 183 SOD1-mutated ALS patients. Mutations were classified as severe or mild according to the median survival of the study population. Patients were screened for the HFE p.H63D polymorphism. Survival was calculated using the Kaplan–Meier modeling, and differences were measured by the log-rank test. Multivariable analysis was performed with the Cox proportional hazards model (stepwise backward). Results: SOD1 severe mutation carriers show more frequent familial history for ALS and shorter survival compared to mild mutation carriers. Carriers and non-carriers of the p.H63D polymorphism did not differ in terms of sex ratio, frequency of positive familial history, age at onset, and bulbar/spinal ratio. In univariate and in Cox multivariable analysis using sex, age at onset, site of onset, family history, country of origin, and mutation severity as covariates, p.H63D carriers had a longer survival (p = 0.034 and p = 0.004). Conclusions: We found that SOD1-mutated ALS patients carrying the p.H63D HFE polymorphism have a longer survival compared to non-carriers, independently of sex, age and site of onset, family history, nation of origin, and severity of mutations, suggesting a possible role as disease progression modifier for the p.H63D HFE polymorphism in SOD1-ALS.

Purpose: High doses of local anesthetic administered intra-articularly and peri-articularly during local infiltration analgesia (LIA) for total knee arthroplasty (TKA) may have potential effects on patient hemodynamics. The aim of this study was to know if hemodynamic changes are associated with LIA in patients undergoing TKA. Methods: In a prospective observational design, elective patients undergoing orthopedic surgery for TKA and treated with LIA consisting of a mixture of ropivacaine (300 mg) and epinephrine (1 mg) were investigated for changes in selected hemodynamic parameters: heart rate (HR), non-invasively registered mean arterial blood pressure (MAP), and incidence of arrhythmias during the perioperative course, consisting of the following periods: period 1. from establishment of spinal anesthesia to prior to LIA administration, period 2. from administration of LIA to before release of ischemia tourniquet, period 3. from release ischemia tourniquet to end of surgery, and period 4. from transfer to the post anesthesia care unit to the ward. Statistical analysis was done with ANOVA-RM for the difference in means in repeated measurements, and with the Tukey Test between pairs. Data are presented as mean ± standard deviation. A P value 0.50), and from period 2 to period 4 (89 ± 13 to 91 ± 11 mmHg, P > 0.50). No arrhythmias were detected during follow-up. Conclusions: A mixture of ropivacaine and epinephrine for LIA, despite the high doses administered, does not have a negative impact on hemodynamics.

Abstract Background Segment fusion using interbody cages supplemented with pedicle screw fixation is the most common surgery for the treatment of low back pain. However, there is still much controversy regarding the use of cages in a stand-alone fashion. The goal of this work is to numerically compare the influence that each surgery has on lumbar biomechanics. Methods A non-linear FE model of the whole lumbar spine was developed to compare between two types of cages (OLYS and NEOLIF) with and without supplementary fixation. The motion of the whole spine was analysed and the biomechanical environment of the adjacent segments to the operated one was studied. Moreover, the risk of subsidence of the cages was qualitatively evaluated. Results A great ROM reduction occurred when supplementary fixation was used. This stiffening increased the stresses at the adjacent levels. It might be hypothesised that the overloading of these segments could be related with the clinically observed adjacent disc degeneration. Meanwhile, the stand-alone cages allowed for a wider movement, and therefore, the influence of the surgery on adjacent discs was much lower. Regarding the risk of subsidence, the contact pressure magnitude was similar for both intervertebral cage designs and near the value of the maximum tolerable pressure of the endplates. Conclusions A minimally invasive posterior insertion of an intervertebral cage (OLYS or NEOLIF) was compared using a stand-alone design or adding supplementary fixation. The outcomes of these two techniques were compared, and although stand-alone cage may diminish the risk of disease progression to the adjacent discs, the spinal movement in this case could compromise the vertebral fusion and might present a higher risk of cage subsidence.

Los trastornos mentales como la depresión, el trastorno de angustia, la ansiedad generalizada, el trastorno obsesivo compulsivo, entre otros, han existido siempre, pero las condiciones de nuestra sociedad relacionados con el mercado, la producción, el conocimiento, etc., implican para las personas unos importantes niveles de exigencia, así como otras formas de relacionarse, con los demás, con la tecnología, volviendo el entorno altamente competitivo, todas esas presiones pueden llevar al límite la salud mental. Esto se evidencia en el creciente número de personas con problemas de salud mental que reportan los entes sanitarios, incluyendo el suicidio dentro de las cifras de mortalidad. Las consecuencias de los problemas mentales también pueden llevar a repercusiones físicas como: dolores musculoesqueléticos, trastornos gástricos, debilitamiento del sistema inmunitario, enfermedad cardíaca y otras afecciones.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both lower and upper motor neurons (MNs) in the central nervous system. ALS etiology is highly multifactorial and multifarious, and an effective treatment is still lacking. Neuroinflammation is a hallmark of ALS and could be targeted to develop new therapeutic approaches. Interestingly, the transcription factor Nurr1 has been demonstrated to have an important role in the inflammatory process in several neurological disorders, such as Parkinson's disease and multiple sclerosis. In the present paper, we demonstrate for the first time that Nurr1 expression levels are upregulated in the peripheral blood of ALS patients. Moreover, we investigated Nurr1 function in the SOD1-G93A mouse model of ALS. Nurr1 was strongly upregulated in the spinal cord during the asymptomatic and early symptomatic phases of the disease, where it promoted the expression of brain-derived neurotrophic factor mRNA and the repression of NFκB pro-inflammatory targets, such as inducible nitric oxide synthase. Therefore, we hypothesize that Nurr1 is activated in an early phase of the disease as a protective endogenous anti-inflammatory mechanism, although not sufficient to reverse disease progression. On the basis of these observations, Nurr1 could represent a potential biomarker for ALS and a promising target for future therapies.

Abstract Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. Repeat expansions have been proposed to cause disease by both the repeat RNA forming foci that sequester RNA‐binding proteins and through toxic dipeptide repeat proteins generated by repeat‐associated non‐ATG translation. GGGGCC repeat RNA folds into a G‐quadruplex secondary structure, and we investigated whether targeting this structure is a potential therapeutic strategy. We performed a screen that identified three structurally related small molecules that specifically stabilise GGGGCC repeat G‐quadruplex RNA. We investigated their effect in C9orf72 patient iPSC‐derived motor and cortical neurons and show that they significantly reduce RNA foci burden and the levels of dipeptide repeat proteins. Furthermore, they also reduce dipeptide repeat proteins and improve survival in vivo, in GGGGCC repeat‐expressing Drosophila. Therefore, small molecules that target GGGGCC repeat G‐quadruplexes can ameliorate the two key pathologies associated with C9orf72 FTD/ALS. These data provide proof of principle that targeting GGGGCC repeat G‐quadruplexes has therapeutic potential.

Una cantidad sustancial de literatura describe cómo la psicología ha estudiado la irracionalidad de la mente humana y sus procesos, pero pocos autores han escrito acerca de cómo el diseño de la diagramación influye en sus procesos de toma de decisiones. Este artículo propone un experimento para analizar cómo los usuarios eligen un producto específico en función de la posición y forma en que se les muestran las opciones (secuencial o simultánea).

Objective: To evaluate the metabolic correlates of lifetime sport practice in ALS through brain 18F-FDG-PET. Methods: 131 patients completed a questionnaire about lifetime exposures, including physical activity related to sports, hobbies and occupations, and underwent brain 18F-FDG-PET. Exposure to sports was expressed as MET (Metabolic Equivalent of Task). We considered only regular practice (at least 2 h/week, for at least three months). We compared brain metabolism between two groups: subjects who did not report regular sport practice during life (N-group) and patients who did (Y-group). The resulting significant clusters were used in each group as seed regions in an interregional correlation analysis (IRCA) to evaluate the impact of lifetime sport practice on brain networks typically involved by the neurodegenerative process of ALS. Each group was compared to healthy controls (HC, n = 40). Results: We found a significant, relative cerebellar hypermetabolism in the N-group compared to the Y-group. The metabolism of such cerebellar cluster resulted correlated to more significant and widespread metabolic changes in areas known to be affected by ALS (i.e. frontotemporal regions and corticospinal tracts) in the N-group as compared to the Y-group, despite the same level of disability as expressed by the ALS FRS-R. Such findings resulted independent of age, sex, site of onset (bulbar/spinal), presence/absence of C9ORF72 expansion, cognitive status and physical activity related to hobbies and occupations. When compared to HC, the N-group showed more widespread metabolic changes than the Y-group in cortical regions known to be relatively hypometabolic in ALS patients as compared to HC. Conclusions: We hypothesize that patients of the N-group might cope better with the neurodegenerative process, since they show more widespread metabolic changes as compared to the Y-group, despite the same level of disability. Nevertheless, further studies are necessary to corroborate this hypothesis.

We investigated whether the C9orf72 repeat expansion is associated with specific clinical features, comorbidities, and prognosis in patients with amyotrophic lateral sclerosis (ALS). A cohort of 1417 ALS patients, diagnosed between January 1, 2009 and December 31, 2013 by 13 Italian ALS Referral Centers, was screened for the C9orf72 repeat expansion, and the analyses were performed comparing patients carrying this expansion (ALS-C9Pos) to those negative for this and other explored ALS-related mutations (ALS without genetic mutations, ALSwoGM). Compared to the ALSwoGM group, ALS-C9Pos patients (n = 84) were younger at disease onset, at the first clinical observation and at diagnosis (p < 0.001). After correcting for these differences, we found that ALS-C9Pos patients had higher odds of bulbar onset, diagnosis of frontotemporal dementia (FTD) and family history of ALS, FTD, and Alzheimer's disease and had lower odds of spinal onset, non-invasive ventilation, hypertension and psychiatric diseases than ALSwoGM patients. Among these variables, those related to shorter survival time were: bulbar onset, presence of FTD, hypertension, psychiatric disease, and family history of ALS (p < 0.05). Cox proportional hazards regression multivariate analysis suggested that carrying the C9orf72 repeat expansion was an independent factor negatively impacting on survival time in men (HR 1.58, 95% CI 1.07–2.33, p = 0.021), but not in women (p > 0.05) as well as in the whole sample (p > 0.05). When compared to ALSwoGM, ALS-C9Pos showed an earlier disease onset, no significant diagnostic delay and a higher odds of bulbar onset, FTD and family history of ALS and dementia. Moreover, male sex drove the negative effect of expanded variant on survival, confirming the hypothesis that sex is likely to be a crucial factor in the biology of C9orf72-related disease.

Los problemas de espalda son una causa frecuente de consulta médica y acarrean múltiplesgastos para los sistemas de salud por concepto de medicamentos, servicios e incapacidades.El National Institute of Neurological Disorders and Stroke (NINDS) señala que los síntomas enla espalda baja incluyen dolor muscular, de tipo disparo o dolor punzante, flexibilidad limitada,disminución del rango de movimiento o incapacidad para mantenerse erguido.De acuerdo con la Organización Mundial de la Salud (OMS), el dolor lumbar es una causa im-portante de discapacidad y se produce en proporciones similares en todas las culturas, interfierecon la calidad de vida y el rendimiento en el trabajo.Este artículo analiza los ejercicios del core como una opción de intervención para el dolor deespalda baja, en cuanto a su descripción, sus efectos sobre el dolor, la función y otras variablesde cualidades físicas.

The socioeconomic burden of amyotrophic lateral sclerosis (ALS) is high, but the projected number of cases in the upcoming years is unclear. Here, the authors estimate the number and distribution of ALS cases to 2040, and show that cases are projected to increase, particularly in developing nations.

This paper proposes a new damage index named degree of health (DoH) to efficiently tackle structural damage monitoring in real-time. As a key contribution, the proposed index relies on a pattern matching methodology that measures the time-of-flight mismatch of sequential ultrasonic guided-wave measurements using fuzzy logic fundamentals. The ultrasonic signals are generated using the transmission beamforming technique with a phased-array of piezoelectric transducers. The acquisition is carried out by two phased-arrays to compare the influence of pulse-echo and pitch-catch modes in the damage assessment. The proposed monitoring approach is illustrated in a fatigue test of an aluminum sheet with an initial notch. As an additional novelty, the proposed pattern matching methodology uses the data stemming from the transmission beamforming technique for structural health monitoring. The results demonstrate the efficiency and robustness of the proposed framework in providing a qualitative and quantitative assessment for fatigue crack damage.

El presente artículo tiene por objetivo problematizar los conceptos de otredad autóctona y otredad idealizada implementados en las artes visuales costarricense a mediados del siglo XIX e inicios del siglo XX, desde una perspectiva iconográfica y poscolonial. Se entiende por otredad autóctona a la representación originaria costarricense y por otredad imaginada a la concepción europea cimentada en la pintura académica costarricense. Para el estudio se confronta la obra de Enrique Echandi (artista costarricense) con la pintura de Tomás Povedano de Arcos (artista europeo). Al final del texto se realiza una reflexión poscolonial respecto al conflicto Echandi vs. Povedano.

El presente artículo analiza la iconografía e ideología de la Pinacoteca de la Asamblea Legislativa de Costa Rica con el fin de comparar los valores simbólicos e ideales de los retratos de Jefes de Estado y Presidentes de la República. Para este caso, se consideran los siguientes aspectos: elaboración pictórica, marco y acopio retratístico en la notafilia. Se toma en consideración los retratos de José María Castro Madriz y Braulio Carrillo Colina para ejemplificar.

Patient-derived induced pluripotent stem cells (iPSCs) provide an opportunity to study human diseases mainly in those cases for which no suitable model systems are available. Here, we have taken advantage of in vitro iPSCs derived from patients affected by amyotrophic lateral sclerosis (ALS) and carrying mutations in the RNA-binding protein FUS to study the cellular behavior of the mutant proteins in the appropriate genetic background. Moreover, the ability to differentiate iPSCs into spinal cord neural cells provides an in vitro model mimicking the physiological conditions. iPSCs were derived from FUSR514S and FUSR521C patient fibroblasts, whereas in the case of the severe FUSP525L mutation, in which fibroblasts were not available, a heterozygous and a homozygous iPSC line were raised by TALEN-directed mutagenesis. We show that aberrant localization and recruitment of FUS into stress granules (SGs) is a prerogative of the FUS mutant proteins and occurs only upon induction of stress in both undifferentiated iPSCs and spinal cord neural cells. Moreover, we show that the incorporation into SGs is proportional to the amount of cytoplasmic FUS, strongly correlating with the cytoplasmic delocalization phenotype of the different mutants. Therefore, the available iPSCs represent a very powerful system for understanding the correlation between FUS mutations, the molecular mechanisms of SG formation and ALS ethiopathogenesis.

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, neurodegenerative disease caused by the degeneration of motor neurons. We report a case of a 45-years-old patient with ALS to underline difficulties and challenges in ALS management. Even though ALS remains fatal, several advances have been made in improving the consequences of this disease: symptomatic treatments have an important role in controlling sialorrhea, bronchial secretions, pseudobulbar emotional lability, cramps, spasticity, depression and anxiety, insomnia and pain. An adequate management of ALS should be multidisciplinar, involving not only the neurologist, but also family physicians and many other specialists, such as pulmonologist, rehabilitation medicine physician, speech therapist, dietitian and psychologist. The multidisciplinary approach should be aimed at relieving specific problems associated with the disability of single patients and improving their quality of life.

Objective: Distinguishing immunoglobulin G4 (IgG4)-related disease ocular involvement (IgG4-ROD) from other non-IgG4 pathologies in the orbit and eyeball is often complex. The objective was to compare clinical, analytical, imaging, and anatomopathological features of IgG4-ROD with other inflammatory and/or autoimmune ocular diseases (non-IgG4-ROD). Methods: An observational, descriptive, and retrospective study included 18 patients diagnosed with IgG4-ROD according to Umehara's 2011 and/or 2020 comprehensive criteria, from 3 centers. Additionally, 12 patients with non-IgG4-ROD between 2014 and 2022 were selected, forming 2 groups. Data collection involved visualizing medical records. Demographic profile, clinical manifestations, analytical, histopathological, and radiological findings were analyzed using SPSS Statistics 19. Categorical variables were presented as frequencies and percentages, and continuous variables as means with standard deviation or median with interquartile range. Proportions were compared using the chi-square test, and means and medians were compared using T-tests and nonparametric tests. A confidence level of a = .05 was selected. Results: Thirty patients were analyzed: 18 with IgG4-ROD and 12 with non-IgG4-ROD. Among the latter, diagnoses included Histiocytosis (n = 4), Amyloidosis (n = 3), malignant secondary malignancy (n = 2), and other conditions (n = 3). Female sex predominated in IgG4-ROD (78% vs. 50%, P = .12). Mean age was 44 years, with no group difference (P = .26). Bilateral involvement was more common in non-IgG4 (92% vs. 72%, P = .21). Predominant symptoms in IgG4-ROD were proptosis, ocular pain, xerophthalmia, palpebral edema, and diplopia, while palpebral edema and ocular motility disturbance were more usual in other pathologies. Proptosis, xerophthalmia, and diplopia were significantly more frequent in IgG4-ROD (P = .042, P = .021, P = .021, respectively). Parotid involvement showed significant association in IgG4-ROD at 33% (P = .031). Statistically significant differences were observed in elevated serum IgG4 levels (67%, P = .002), IgG (P = .037), and IgG2 levels = 5.3 g/L (56%, P = .023) in IgG4-ROD. There was also a significant difference between the association of eosinophilia and the non-IgG4 group (67% vs. 22%, P = .034), as did mean serum IgG value and the IgG4-ROD group (P = .037). Lacrimal gland involvement associated with IgG4-ROD (P = .032). Histopathologically, IgG4-ROD showed significant associations with lymphoplasmacytic infiltrate (100%, P = .004), storiform fibrosis (36%, P = .05), and presence of Eosinophils (64%, P = .003). Conclusion: Immunoglobulin G4-related ophthalmic disease showed significant associations with xerophthalmia, proptosis, diplopia, and parotid involvement. Elevated serum IgG4, IgG, and IgG2 levels were also linked to this condition. Imaging studies revealed lacrimal gland involvement. Furthermore, lymphoplasmacytic infiltrate, storiform fibrosis, and eosinophil presence were significant in histopathological findings. Conversely, serum eosinophilia, bilateral involvement, and palpebral edema in imaging studies were statistically related to the non-IgG4 group. [ABSTRACT FROM AUTHOR]